Novel 2,6-disubstituted phenyl-aminoguanidine compounds

ABSTRACT

The invention relates to compounds of the general formula: ##EQU1## in which one double bond is present between the carbon atom of the guanidine moiety and one of the adjacent nitrogen atoms and 
     R 0  stands for hydrogen, halogen, hydroxy, alkoxy or alkyl (1 to 6 C), 
     R 1 , r 2  for halogen, hydroxy, alkyl (1 to 4 C) or alkoxy (1 to 4 C), 
     R 3 , r 3  &#39;, r 3  &#34; for hydrogen or alkyl (1 to 4 C) on the understanding that one of the substituents R 3 , R 3  &#39; or R 3  &#34; is absent because of the presence of the double bond, 
     R 4  for hydrogen, alkyl (1-4 C), hydroxy, alkoxy (1-4 C) or amino optionally substituted with one or two alkyl (1 to 4 C) groups, 
     R 5 , r 6  for hydrogen, alkyl (1-6 C), acyl or R 5  + R 6  together represent an alkylidene, cyclic alklidene or aralkylidene group, 
     As well as the acid addition salts thereof, provided that, if R 4  stands for methyl and R 0 , R 3 , R 3  &#34;, R 5  and R 6  for hydrogen, R 1  and R 2  may not represent methyl simultaneously, having a strong and long-acting anti-hypertensive activity.

The invention relates to 1-phenyl-2-aminoguanidine derivatives, thephenyl of which being substituted at the positions 2 and 6, to processesfor the preparation of these compounds and to pharmaceuticalpreparations containing these compounds as the active components.

Surprisingly, it has been found that compounds of the general formula:##EQU2## in which one double bond is present between the carbon atom ofthe guanidine moiety and one of the adjacent nitrogen atoms and

R₀ stands for hydrogen, halogen, hydroxy, alkoxy or alkyl (1to 6 C),

R₁,r₂ for halogen, hydroxy, alkyl (1to 4 C) or alkoxy (1 to 4 C),

R₃, r₃ ', r₃ " for hydrogen or alkyl (1 to 4 C), on the understandingthat one of the substituents R₃, R₃ ' or R₃ " is absent because of thepresence of the double bond,

R₄ for hydrogen, alkyl (1-4 C), hydroxy, alkoxy (1-4 C) or aminooptionally substituted with one or two alkyl (1 to 4 C) groups,

R₅, r₆ for hydrogen, alkyl (1-6 C), acyl or R₅ + R₆ together representan alkylidene, cyclic alkylidene or aralkylidene group,

As well as the acid addition salts thereof, provided that, if R₄ standsfor methyl and R₀, R₃, R₃ ", R₅ and R₆ for hydrogen, R₁ and R₂ may notrepresent methyl simultaneously, possess valuable biological activities.

The compounds according to the invention have a strong and long-actinganti-hypertensive activity, even upon oral administration. Unlike manyother compounds which produce a blood pressure lowering effect throughan adrenergic neuron blocking activity, the present compounds actdirectly upon the blood pressure regulating centres of the centralnervous system without inducing strong sedative side-effects whichusually render the use of centrally active anti-hypertensive compoundsless desirable.

The compounds according to the general formula I can be prepared by anymethod commonly used for this type of compounds.

The compounds I may be prepared, for example, by condensation of thecyanamide or the corresponding carbo-diimide of the general formula II:##EQU3## or an acid addition salt thereof, in which R₀, R₁, R₂, R₃ andR₄ have the meaning mentioned above and in which an extra bond ispresent between the carbon atom and one of the adjacent nitrogen atomsso that either R₃ or R₄ is absent, with hydrazine or a hydrazinederivative of the general formula III: ##EQU4## or an acid addition saltthereof, in which R₃ ", R₅ and R₆ have the meaning mentioned above.

The compounds I may further be prepared by condensation of an O- orS-alkyliso(thio)urea of the general formula IV: ##EQU5## or an acidaddition salt thereof, in which R₀, R₁, R₂, R₃, R₃ ' and R₄ have theaforesaid meanings and in which an extra bond is present between thecarbon atom and one of the adjacent nitrogen atoms, so that either R₃ orR₃ ' is absent, X is oxygen or sulphur and R stands for lower alkyl,preferable methyl or ethyl, with hydrazine or a hydrazine derivativeaccording to the general formula III or an acid addition salt thereof.

The compounds I can moreover be prepared by condensation of a O- orS-alkyliso(thio)-amino urea of the general formula V: ##EQU6## or anacid addition salt thereof, in which R₀, R₁, R₂, R₃, R₃ ", R₅, R₆, X andR have the aforesaid meanings and in which an extra bond is presentbetween the carbon atom and one of the adjacent nitrogen atoms, so thateither R₃ or R₃ " is absent, with an amine or amine derivative of thegeneral formula VI: ##EQU7## or an acid addition salt thereof, in whichR₃ ' and R₄ have the meaning mentioned above.

The latter method is preferably used if it is intended to prepare acompound I in which R₄ represents a hydroxy-, alkoxy- or amino-group.

The starting materials required in the aforesaid syntheses, particularlythe starting materials of the general formulae II, IV and V are preparedin a way commonly used for this kind of compounds. For the sake ofcompleteness some conventional methods in preparing these startingmaterials are schematically described in the reaction scheme shown inthe accompanying drawings.

The reaction of the starting material II or IV with a hydrazine offormula III or the reaction of the starting material V with an amine oramine derivative of formula VI is preferably performed at a temperaturevarying between room- and the boiling temperature of the preferablyinert solvent used.

Examples of hydrazines according to formula III which may be used in theabove mentioned condensation reactions; are for example hydrazine,methylhydrazine, N,N'-dimethylhydrazine, N,N-diethylhydrazine,N-methyl-N'-propylhydrazine, N-methyl-N'-isopropylidenehydrazine,N-ethyl-N',N'-dimethylhydrazine, etc., as well as the acid additionsalts thereof.

Examples of amines or amine derivatives that can be used in thecondensation reaction with the starting material V are for exampleammonia, methylamine, ethylamine, dimethylamine, diethylamine,isopropylamine, isobutylamine, but more particularly hydrazine,methylhydrazine, N,N-dimethylhydrazine, N,N'-dimethylhydrazine,N,N-diethylhydrazine, N-methyl-N'-propylhydrazine,N-methyl-N'-isopropylidene-hydrazine, N-ethyl-N',N'-dimethylhydrazine,hydroxylamine, hydroxylaminemethylether, N-methylhydroxylamine,hydroxylamine-ethylether, hydroxylamine-propylether,N-isopropylhydroxylamine, N-methylhydroxylamine-methylether, etc., aswell as the acid addition salts thereof.

In general, the optional substituents at the phenyl ring (R₀), at thenitrogen atoms (R₃, R₃ ', R₃ ", R₄, R₅, R₆) and/or at the oxygen atom(R₄ = alkoxy) of the final product I are preferably present already inone of the aforesaid starting products. However, it is also possible tointroduce or to modify these substituents in the product obtained afterthe aforesaid condensation reactions. For example, the N-hydroxy groupof a compound I (R₄ = OH) can be alkylated in a usual manner with analkylating agent such as diazomethane, diazoethane or dimethylsulphateor by means of a Williamson synthesis. The nitrogen atom of the 2-aminogroup of a compound I may be acylated, e.g., with an acylhalide oranhydride, or may be alkylated, e.g., with an alkylhalide or by means ofa reduction of the corresponding acyl group in the usual manner. Certainsubstituents at the phenyl moiety of a compound I can furthermore beconverted into another substituent; for example of hydroxyl group can beconverted in a conventional manner into an alkoxy group, a methoxy groupinto a hydroxyl group, etc.

A reaction which is performed preferably after the condensation reactionmentioned above consists of the conversion of a final compound I, inwhich both R₅ and R₆ stand for hydrogen, into a compound I, in which R₅and R₆ together represent an alkylidene, cyclo alkylidene oraralkylidene group in a conventional manner by reacting a compound I (R₅and R₆ = H) with an aliphatic, cyclo-aliphatic or aromatic aldehyde orketone. In this connection aliphatic aldehydes or ketones with 1-6carbon atoms as formaldehyde, acetaldehyde, propanal, 2-butanone, 2- or3-pentanone and, in particular, acetone, the cyclo-aliphatic aldehydesor ketones with 5-12 carbon atoms such as cyclopentanone, cyclohexanone,4-methyl-cyclohexanone, cyclooctanone, 1-cyclohexyl-3-pentanone or1-cyclohexylpropanone, and the aromatic aldehydes or ketones with 7 to12 carbon atoms in which the aromatic group is a phenyl group, such asbenzaldehyde, phenyl-acetaldehyde, 1-phenylpropanone or1-phenyl-3-pentanone, are to be preferred.

Compounds I having an acylated 2-amino moiety (R₅ or R₆ = acyl) are alsopreferably prepared by acylating a compound I in which R₅ or R₆ ishydrogen. The acyl group used is preferably derived from a loweraliphatic or araliphatic carboxylic acid or from a carbamic acid, suchas acetic acid, propionic acid, phenyl acetic acid, carbamic acid,N-methylcarbamic acid or N,N-diethylcarbamic acid.

The compounds of formula I are obtained as the free base or as an acidaddition salt dependent on the reaction conditions, in which they areprepared. If desired, the free base I can be prepared from the salt I,for example, by reaction with an alkaline compound or by means of anion-exchanger, and the free base I can be converted into an acidaddition salt I in the usual manner.

Pharmaceutically acceptable acid addition salts are obtained bycontacting the free base I with organic or inorganic acids such ashydrochloric acid, HBr, HJ, sulphuric acid, phosphoric acid, aceticacid, propionic acid, glycollic acid, maleic acid, fumaric acid, malonicacid, succinic acid, tartaric acid, lactic acid, citric acid, ascorbicacid, salicylic acid, benzoic acid.

The compounds according to the invention can be administered orally aswell as parenterally, preferably in a daily dose of fron 0.001 to 50 mgper kg body weight. For this purpose the compounds are incorporated intoa suitable dosage form for oral or parenteral administration, forexample, a tablet, pill, capsule, solution, suspension, emulsion, in amanner commonly applied for other biologically active compounds.

A dosage form for oral administration is preferred.

Compounds I which are to be preferred in view of their markedantihypertensive activity are those compounds of formula I, in which(whether or not in combination):

-- R₁ and R₂ stand for halogen or alkyl, especially those compounds inwhich both R₁ and R₂ represent halogen.

-- R₀ stands for a substituent selected from halogen or alkoxy atposition 4 of the phenyl ring (para position with respect to theguanidino moiety).

-- R₅ and R₆ stand for hydrogen or together for an alkylidene,aralkylidene or cyclo-alkylidene moiety.

-- R₃, R₃ ' and R₃ " stand for hydrogen.

-- R₄ represents hydrogen or alkyl.

EXAMPLE I 1-(2,6-dichlorophenyl)-2-aminoguanidine salts

47.4 gram of 1-(2,6-dichlorophenyl)-2-methyl-isothiourea.HJ is suspendedin 66 ml of ethanol. To this suspension is added 6.55 ml of hydrazinehydrate after which the mixture is refluxed for 48 hours. The mixture isthen cooled down and the precipitate formed is filtered off andrecrystallized from ethanol/ether.

Yield: 30.4 g; melting point HJ salt: 208°-210°C.

The HCl salt is obtained by converting the hydro-iodide obtained intothe free base and treating the free base with a methanolic HCl-solution.

Melting point HCl salt: 280°-283°C.

By treating the free base with maleic acid the corresponding maleate isobtained.

Melting point maleate: 168°-170°C.

EXAMPLE II

In the same manner as described in Example I are prepared bycondensation of a hydrazine with1-(2,6-dichlorophenyl)-2-methyl-isothiourea.HJ:

1-(2,6-dichlorophenyl)-2-methylaminoguanidine.HJ; melting point:220°-221°C

1-(2,6-dichlorophenyl)-2-dimethylaminoguanidine.HCl; melting point:>280°C

1-(2,6-dichlorophenyl)-2-methyl-2-dimethylaminoguanidine; Rf inmethanol:acetic acid (98:2) = 0.55 on SiO₂

1-(2,6-dichlorophenyl)-2-isopropylideneaminoguanidine.HCl; meltingpoint: 205°-210°C

1-(2,6-dichlorophenyl)-2-isopropylamino-guanidine.HCl; melting point:227°-228°C

EXAMPLE III A. 1-(2,6-dichlorophenyl)-2,3-dimethyl-isothiourea.HCl

13.0 g of 1-(2,6-dichlorophenyl)-2-methylthiourea are dissolved in 115ml of methanol after which 5.4 ml of methyliodide are added. The mixtureis refluxed for 2.5 hours and then cooled down. By adding ether to themixture a precipitate is obtained that is filtered off.

Yield: 18.9 g; melting point HJ salt: 180°-183°C.

Melting point HCl salt: 173°-175°C.

B. 1-(2,6-dichlorophenyl)-2-amino-3-methylguanidine.HCl

12.7 g of the HCl salt obtained in A. are dissolved in 23 ml of methanolafter which 2.2 ml of hydrazine.hydrate are added. The mixture isrefluxed for 6 days and then evaporated to dryness. With the aid ofcolumn chromatography (SiO₂, eluted with chloroform:methanol 8:2) theresidue is purified and recrystallized from isopropanol/ether.

Yield: 5 g; melting point: 162°-164°C.

C. In the same manner as described in (B).1-(2,6-dichlorophenyl)-2,3-dimethyl-isothiourea (prepared from (A) bytreatment with KOH) is converted with 1,1-dimethylhydrazine,1,2-dimethylhydrazine and ethylhydrazine respectively into:

1-(2,6-dichlorophenyl)-2-dimethylamino-3-methylguanidine (oil);

1-(2,6-dichlorophenyl)-2-methyl-2-methylamino-3-methylguanidine (oil);and

1-(2,6-dichlorophenyl)-2-ethylamino-3-methylguanidine (oil).

Rf in methanol:acetic acid (98:2), 0.70, 0.65 and 0.68 on SiO₂respectively.

EXAMPLE IV 1-(2,6-dimethylphenyl)-2-amino-guanidine.HCl

6.4 g of 1-(2,6-dimethylphenyl)-2-methyl-isothiourea.HJ are dissolvedwhile heating in 10 ml of ethanol to which 1 ml of hydrazine.hydrate hasbeen added. The mixture is refluxed for 18 hours and then cooled. Byadding 20 ml of ether to the mixture a precipitate is formed which isfiltered off.

Yield: 5.2 g; melting point HJ salt: 151°-153°C.

This hydroiodide is converted into the corresponding hydrochloride in aconventional manner. Melting point: 192°-193°C.

EXAMPLE V 1-(2-chloro-6-methylphenyl)-2-amino-guanidine.HCl

6.8 g of 1-(2-chloro-6-methylphenyl)-2-methyl-isothiourea.HJ (meltingpoint: 183°-184°C) are suspended in 10 ml of ethanol to which 1 ml ofhydrazine.hydrate has been added. The mixture is refluxed for 22 hoursand then evaporated to dryness. The residue (oil) is recrystallized fromethanol/ether.

Yield: 5.3 g; melting point HJ salt: 183°-184°C, melting point HCl salt:239°-241°C.

In a corresponding manner1-(2-chloro-6-methylphenyl)-2-dimethyl-amino-guanidine is obtained byreaction with 1,1-dimethylhydrazine.

Starting from the hydroiodide of 1-phenyl-2-methyl-isothioureaderivatives with various phenyl substituents the following compounds areprepared in the same manner as described above:

1-(2,6-dichloro-4-iodophenyl)-2-aminoguanidine.HCl; melting point HClsalt: 229°-231°C

1-(2,6-dimethoxy-phenyl)-2-aminoguanidine; melting point HCl salt:179°-180°C

1-(2-chloro-4,6-dimethoxy-phenyl)-2-aminoguanidine; melting point HClsalt: 193°-194°C

1-(2,6-dihydroxy-phenyl)-2-aminoguanidine

1-(2,6-dichloro-4-hydroxy-phenyl)-2-aminoguanidine.

EXAMPLE VI 1-(2,6-dichlorophenyl)-2-isopropylidene-aminoguanidine.HCl

2.0 g of 1-(2,6-dichloro-phenyl)-2-aminoguanidine.HCl (Example I) aresuspended in 4 ml of glacial acetic acid, after which 0.85 ml of acetoneis added. The mixture is stirred for 20 hours at room temperature. Byadding 10 ml of ether to the mixture a precipitate is obtained that isrecrystallized from ethanol/ether.

Yield: 2g; melting point: 208°-210°C.

In a corresponding manner the following compounds are prepared:

1-(2,6-dichlorophenyl)-2-benzylidene-aminoguanidine.HCl; melting point:216°-217°C

1-(2,6-dichlorophenyl)-2-(2,6-dichlorobenzylidene)aminoguanidine.HCl;melting point: 230°-231°C

1-(2,6-dichlorophenyl)-2-cyclohexylidene-aminoguanidine.HCl; meltingpoint: 140°-155°C

1-(2,6-dichlorophenyl)-2-cyclooctylidene-aminoguanidine.HCl; meltingpoint: 120°-135°C.

EXAMPLE VII 1-(2,6-dimethylphenyl)-1-methyl-2-aminoguanidine.HCl

To 8.2 g of 1-(2,6-dimethylphenyl)-1-methylcyanamide dissolved in 30 mlof ethanol, 3.4 g of hydrazine.hydrochloride are added. The mixture isrefluxed for 20 hours followed by evaporation. The residue isrecrystallized from ethanol/ether.

Yield: 7.8 g; melting point: 187°-188°C.

By using 1.1-dimethyl-hydrazine instead of hydrazine.hydrochloride1-(2,6-dimethylphenyl)-1-methyl-2-dimethylaminoguanidine is obtained asan oily substance.

Rf in methanol:acetic acid (98:2) = 0.63 (SiO₂).

In the same manner as described above is prepared the compound1-(2,6-dichlorophenyl)-1-methyl-2-aminoguanidine.HCl; melting point:124°-125°C.

EXAMPLE VIII 1-(2,6-dimethylphenyl)-2-amino-2-methylguanidine and1-(2,6-dimethylphenyl)-2-methyl-aminoguanidine

5.7 g of 2,6-dimethylphenylcyanamide are dissolved in 25 ml of ethanol,after which 3.2 g of methylhydrazine are added. The mixture is refluxedfor 20 hours and then evaporated. The remaining oil consists of twoisomers. By means of a silica gel column both substances are separated.The compound 1-(2,6-dimethylphenyl)-2-methyl-aminoguanidine (oil) isobtained by elution with chloroform:methanol (8:2); yield: 0.7 g.

Rf in methanol:acetic acid (98:2) = 0.62 on SiO₂ and the compound1-(2,6-dimethylphenyl)-2-amino-2-methylguanidine (oil) by elution withchloroform:methanol (6:4); yield: 1.8 g.

Rf in methanol:acetic acid (98:2) = 0.54 on SiO₂. The HCl salt of thelatter compound melts at 225°-226°C.

EXAMPLE IX

In the same manner as described in Example VII or VIII and starting from2,6-dimethylphenylcyanamide or 2,6-dichlorophenylcyanamide the followingcompounds are obtained:

1-(2,6-dichlorophenyl)-2-aminoguanidine.HCl, melting point: 281°C,

1-(2,6-dichlorophenyl)-2-methyl-aminoguanidine.HJ, melting point:220°-222°C,

1-(2,6-dichlorophenyl)-2-isopropylidene-aminoguanidine.HCl, meltingpoint: 208°-209°C,

1-(2,6-dimethylphenyl)-2-aminoguanidine.HCl, melting point: 192°-193°C.

EXAMPLE X 1-(2,6-dichlorophenyl)-2-amino-3-methylguanidine.HCl

To 4 g of N-(2,6-dichloropheyl)-N'-methylcarbodiimide dissolved in 10 mlof absolute ethanol 1.35 g of hydrazine.hydrochloride is added. Themixture is stirred for 20 hours at room temperature and then evaporatedto dryness. The residue is recrystallized from ethanol/ether.

Yield: 2.5 g; melting point: 162°-164°C.

In a corresponding manner are prepared the free bases:1-(2,6-dichlorophenyl)-2-methylamino-3-methylguanidine and1-(2,6-dichlorophenyl)-2-amino-2,3-dimethylguanidine.

EXAMPLE XI 1-(2,6-dichlorophenyl)-2,3-diamino-guanidine.HCl

10 g of 1-(2,6-dichlorophenyl)-2-methyl-isothiosemicarbazide (oil)obtained from the corresponding HJ-salt (melting point 154°-155°C) bytreatment with an equivalent quantity of KOH, are dissolved in 20 ml ofethanol. To this mixture 2.7 g of hydrazine.hydrochloride are added,after which the mixture is refluxed for 20 hours. After cooling themixture, 50 ml of chloroform are added and stirred for some minutes. Theprecipitate formed is then filtered off.

Yield after recrystallization from isopropanol: 3 g.

Melting point: 179°-180°C.

EXAMPLE XII 1-(2,6-dichlorophenyl)-2-amino-3-hydroxy-guanidine

6.5 g of 1-(2,6-dichlorophenyl)-2-methylisothio-semicarbazide aredissolved in a mixture of 13 ml of ethanol and 0.9 g of hydroxylamine.The mixture is refluxed for 20 hours. After the evaporation of themixture the residue obtained is purified by means of columnchromatography (SiO₂, elution with chloroform:methanol 8:2).

Yield: 2.5 g (oil); Rf in methanol:acetic acid (98:2) = 0.63 on SiO₂.

EXAMPLE XIII

In the manner as described in Example XI are obtained:

A. 1-(2,6-dichlorophenyl)-2-amino-3-methylguanidine.HCl by reaction of1-(2,6-dichlorophenyl)-2-methylisothiosemicarbazide withmethylamine.HCl.

Melting point: 161°-163°C.

B. 1-(2,6-dichlorophenyl)-2-amino-guanidine.HCl by reaction of1-(2,6-dichlorophenyl)-2-methylisothiosemicarbazide withammoniumchloride.

Melting point: 280°C.

C. 1-(2,6-dichlorophenyl)-2-methyl-aminoguanidine.HJ by reaction of1-(2,6-dichlorophenyl)-2(S)-methyl-3-methylaminoisothiourea.HJ withammoniumiodide.

Melting point: 220°-222°C.

D. 1-(2,6-dimethylphenyl)-1-methyl-2-aminoguanidine.HCl by reaction of1-(2,6-dimethylphenyl)-1-methyl-2(S)-methyl-3-aminoisothiourea withammoniumchloride.

Melting point: 186°-188°C.

EXAMPLE XIV 1-(2,6-dichloro-4-tolyl)-2-aminoguanidine.HJ

A. 1-(2,6-dichloro-4-tolyl)-3-benzoylthiourea

To a solution of 10.6 g of 2,6-dichloro-4-toluidine in 80 ml of acetonea freshly prepared solution of benzoylisothiocyanate, obtained from 5.2g of NH₄ CNS + 7.1 ml of benzoylchloride in 120 ml of acetone is added,after which the mixture is refluxed for 1 hour. The mixture is thencooled down and the precipitate formed is removed by filtration. Thefiltrate is evaporated in vacuo. The residue dissolved in 90 ml ofacetone is then poured out into 800 ml of water. A precipitate is formedwhich is filtered off and recrystallized from 750 ml of methanol.

Yield: 9.75 g; melting point: 184°-185°C.

B. 1-(2,6-dichloro-4-tolyl)-thiourea

9 g of the product obtained in (A) are refluxed for 5 minutes with 113ml of 2.5 N NaOH. The mixture, cooled down to ambient temperature, isthen acidified with 22.5 ml of 36% HCl to pH 4 and then made alkalinewith 25% NH₄ OH (1.4 ml) to pH 8. The precipitate obtained in thismanner is sucked off, washed with water and dried in vacuo.

Yield: 6 g; melting point: 220°-222°C.

C. 1-(2,6-dichloro-4-tolyl)-2-methylisothiourea.HJ

5.9 g of the product obtained in (B) are suspended in 49 ml of methanol,after which 2.5 ml of methyliodide are added. The mixture is thenrefluxed for 2.5 hours, and after that cooled down and evaporated invacuo. The residue is titurated after that with 50 ml of ether, driedand recrystallized from ethanol/ether.

Yield: 72. g; melting point: 198°-199°C.

D. 1-(2,6-dichloro-4-tolyl)-2-aminoguanidine.HJ

To 7.18 g of 1-(2,6-dichloro-4-tolyl)-2-methylisothiourea.HJ (C),suspended in 26 ml of ethanol, 1.3 ml of hydrazine.hydrate is addedafter which the mixture is refluxed for 20 hours. The precipitate formedis filtered off and the filtrate evaporated to dryness. Yield: 6.35 g.Melting point HJ salt: 203°-205°C; melting point HCl salt: 149°-150°C.

EXAMPLE XV 1-(2,6-dichlorophenyl)-2-formylaminoguanidine.HCl

10.4 g of 1-(2,6-dichlorophenyl)-2-aminoguanidine.HCl is suspended into10 ml of formic acid, after which the mixture is stirred for 20 hours atambient temperature. A residue that is obtained by adding 50 ml of etherto the mixture is filtered off and dried.

Yield: 10.3 g; melting point: 182°-183°C.

In the conventional manner the following acyl derivatives are obtained:

1-(2,6-dichlorophenyl)-2-acetylaminoguanidine.HCl; melting point HCl:223°-225°C.

1-(2,6-dichlorophenyl)-2-phenylacetylaminoguanidine

1-(2,6-dimethylphenyl)-2-acetylaminoguanidine.

I claim:
 1. A compound selected from the group consisting of a compoundof the formula: ##EQU8##and the pharmaceutically acceptable acidaddition salts thereof, in which one double bond is present between thecarbon atom of the guanidino moiety and one of the adjacent nitrogenatoms, and in which R_(o) is selected from the group consisting ofhydrogen, halogen, hydroxy, alkoxy containing from 1 to 6 carbon atoms,and alkyl containing from 1 to 6 carbon atoms;R₁ and R₂ are selectedfrom the group consisting of halogen, hydroxy, alkyl containing from 1to 4 carbon atoms, and alkoxy containing from 1 to 4 carbon atoms; R₃,r₃ ' and R₃ " are selected from the group consisting of hydrogen andalkyl containing from 1 to 4 carbon atoms, with the proviso that one ofthe substituents R₃, R₃ ' or R₃ " is absent because of the presence ofthe double bond; R₄ is selected from the group consisting of hydrogen,alkyl containing from 1 to 4 carbon atoms, hydroxy, alkoxy containingfrom 1 to 4 carbon atoms, and amino optionally substituted with one ortwo alkyl groups containing from 1 to 4 carbon atoms; R₅ and R₆ togetherrepresent an alkylidene group with 1-6 carbon atoms, a cycloalkylideneor cycloalkyl-alkylidene group with 5-12 carbon atoms or aphenylalkylidene group with 7-12 carbon atoms.
 2. A compound accordingto claim 1, in which R₁ and R₂ are both halogen.
 3. A compound accordingto claim 1, in which the nitrogen atoms of the guanidino moiety (R₃, R₃', R₃ ") are unsubstituted.
 4. A compound selected from the groupconsisting of 1-(2,6-dichlorophenyl)-2-isopropylidene-aminoguanidine andthe pharmaceutically acceptable acid addition salts thereof.